I keep my handguns loaded and in the safe...all handguns always loaded. gun(s) are not always in safe, but that is where they end up
The problem with this is that the interior of your safe can get hot enough to cook off ammo. When you add a chambered weapon to the mix, it may fire. Since most gun safes use relatively little steel, you run the risk of somebody getting shot.
This isn't to say that you should unload the guns, but you should be mindful of this fact, and orient them accordingly. Keep them pointed in a safe direction, even inside the safe.